The long-term goal of this project is to understand mechanisms of mutual recognition between axons and particular cellular target domains as synapses assemble and stabilize into mature contacts. In the previous funding period, it was determined that F-actin cytoskeleton anchors the entire immature trans-synaptic adhesive scaffold, to which classic cadherins contribute, while mature synapse structure requires neither F-actin or cadherins. At the same time, changes in cadherins and actin at mature synapses can dramatically affect synapse plasticity and spine shape. These and other findings form a conceptual framework for cadherin action that extends from target recognition to distinct phases of synapse maturation and plasticity. The Aims proposed for the next funding period address first how and when cadherins contribute to synapse structure as synapses are first formed and how this is modified as synapses mature. This will be determined using cell biological, ultrastructural and biochemical approaches. Then the functional relationship between cadherins and laminar and regional targeting, and the contribution of cadherins to matching pre- and postsynaptic sites will be determined using organotypic and dissociated neuron cultures. The focus is on the cadherin family because they are excellent candidate molecules to confer synapse adhesion, adhesion-based signaling and synapse recognition. The mechanisms underlying synapse targeting and assembly have great clinical significance for understanding and treating developmental disorders as well as for stimulating the regeneration of useful connectivity following injury.